Treatment of hyperproliferative conditions of body surfaces

ABSTRACT

The present invention relates to pharmaceutical formulations comprising an anthracycline and the uses thereof for treatment of clinical conditions of body surfaces such as skin and mucosal membranes, wherein abnormal cell differentiation and/or hyperproliferation is a primary factor of the pathogenesis. In particular the invention relates to treatment of psoriasis, and preferably to treatment of psoriasis with valrubicin topically applied.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations comprisingan anthracycline and the uses thereof for treatment of clinicalconditions of body surfaces such as skin and mucosal membranes, whereinabnormal cell differentiation and/or hyperproliferation is a primaryfactor of the pathogenesis.

BACKGROUND OF THE INVENTION

Anthracyclines

Anthracyclines are antibiotics having potent antineoplastic activity,and accordingly they have been used in the treatment of a variety ofcancers. The cytostatic effect of most anthracyclines is achieved byaffecting DNA functions for example inhibition of RNA synthesis usuallyby intercalating with DNA.

The group of anthracyclines for example comprises doxorubicin,valrubicin, epirubicin, daunorubicin and idarubicin. Doxorubicin andepirubicin have been applied against a broad spectrum of neoplasticdiseases, whereas daunorubicin has primarily been applied against acuteleukemia. Doxorubicin, daunorubicin, idarubicin and epirubicin areusually administered systemically by injection. Systemic administrationof these anthracyclines, however results in a number of undesirable sideeffects such as cardiotoxicity and bone marrow suppression.

Anthracyclines are in general known to be very tissue toxic. Forexample, paravenous injection of epirubicin results in severe necrosisand immediate measures have to be undertaken to avoid severe localtoxicity.

Valrubicin is a semisynthetic analogue of doxorubicin and it isdeveloped for the treatment of superficial bladder cancer and approvedfor such use in the United States. Usually a total of 800 mg isadministered by 40 mg/ml intravesical instillation of two hours durationfor a total of 6 times once a week. Such a treatment does not result insystemic uptake, but valrubicin may be found in an effectiveconcentration 1800 μm into the epithelium of the bladder (7).

Psoriasis

Psoriasis is characterised by epidermal hyperproliferation including ahighly increased growth of keratinocytes. Furthermore, parakeratosis,i.e. cell nuclei retained in stratum corneum may always be observed inpsoriatic patients. With increased cell proliferation, there is anincreased DNA synthesis in the affected tissue which has been the basisfor assays for evaluation of the efficacy of anti-psoriasis agents.

Treatment of psoriasis depends on the kind of psoriasis and the degreeof severity of the psoriasis to be treated. Psoriasis vulgaris, guttatepsoriasis, flexural psoriasis, erythrodermic psoriasis, generalisedpustular psoriasis and localised pustular psoriasis are the most commonforms of the disease.

Commonly used treatments against psoriasis may for example be

-   -   Local treatment with vitamin-D derivative ointments or creams.        Vitamin D is slow working and can cause temporary skin        irritation.    -   Local treatment with steroid ointments that may inhibit        inflammation associated with psoriasis. Common side effects of        steroids include thinning of the skin, easy bruising and stretch        marks. Furthermore, administration of steroids often results in        rebound phenomena.    -   Coal tar ointment or coal tar baths that may inhibit        inflammatory processes in the skin. Coal tar may make the skin        more sensitive to ultraviolet light and tar products stain        clothing and linens, and may be irritating to the skin.    -   Potassium-permanganate baths that have a disinfecting effect.    -   Climatotherapy, for example sunbathing and bathing in saltwater        for example at the Dead Sea. However 10% of psoriatic patients        are hypersensitive against sunlight and sunburn can cause        psoriasis to get worse. Furthermore, sunbathing increases the        risk of skin cancer.

These treatments are frequently not effective and especially more severecases of psoriasis cannot be treated using the above mentionedtreatments. More severe cases of psoriasis may instead be treated withlight therapy which, however, must be performed at the hospital orclinic. Light therapy can for example be:

-   -   Ultraviolet light treatment (UVB), which especially is applied        in cases where the psoriasis is widespread, but not very thick,        because UVB can not penetrate a thick layer.    -   Ultraviolet light and tablet treatment (PUVA) that is a combined        treatment involving administration of 8-methoxypsoralen that        increases the sensitivity of the skin towards UVA therapy and        therapy with UVA. The side effects of this treatment involve        nausea and in certain cases increased biochemical liver values.        Moreover UVA irradiation results in an increased risk of skin        cancer and premature ageing of the skin

Very severe cases of psoriasis that may not be effectively treated witheither of the above mentioned treatments may be treated with a systemictreatment agent such as for example:

-   -   Methotrexate—a cytostatic, which is also used in the treatment        of cancer. The dose is lower than what is used in cancer        treatment. Short-term side effects of methotrexate include        nausea, fatigue, loss of appetite and mouth sores, whereas        long-time side effects may include damages to the liver.    -   Sandimmun/cyclosporin—an immune inhibiting compound that is also        used in organ transplantation that inhibits the abnormal immune        processes in the skin of psoriatic patients. Side effects may be        severe. They are similar to the side effects caused by other        cytotoxic agents and include myelosuppression, decreased        resistance to infections and risk of secondary neoplasms.    -   Acitretin—a vitamin A like compound that inhibits inflammation.        Acitretin is only effective against pustular and erythrodermic        types of psoriasis, and increases the risk of causing birth        defects in developing fetuses.

The side effects of these treatments are considerable and hence it isnot desirable to use any of these treatments to frequently.

SUMMARY OF THE INVENTION

Accordingly, there is a great need for new improved treatments againstpsoriasis that are effective, but do not cause adverse side effects.

Cytostatic compounds such as methotrexate used to treat psoriasis mustbe administered systemically in order to be effective. Systemicadministration results in an increased risk of side effects, some ofwhich may be severe. No effective cytostatic compound is currentlyavailable that may be applied topically to the site of disease withoutcausing local toxicity to the skin.

The present invention discloses that a number of cytostatic compounds,namely members of the group of anthracyclines as well as derivativesthereof, may be used in topical formulations for the treatment ofpsoriasis and other clinical conditions of body surfaces, whereinhyperproliferation is a primary factor of the pathogenesis.

Hence it is a first objective of the present invention to providepharmaceutical compositions comprising an anthracycline and/or aderivative thereof together with one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical condition is formulated fortopical administration to a body surface.

It is a second objective of the present invention to provide methods oftreatment of a condition associated with hyperproliferation orpre-neoplastic or neoplastic processes of a body surface in anindividual in need thereof comprising administering a pharmaceuticalcomposition comprising an anthracycline topically to said individual.

It is a third objective of the present invention to provide uses ofpharmaceutical composition comprising an anthracycline for thepreparation of a medicament for the treatment of a condition associatedwith hyperproliferation or pre-neoplastic or neoplastic processes of abody surface.

LEGENDS TO FIGURES

FIG. 1: Day 0, psoriatic plaque on left elbow of a patient prior totreatment.

FIG. 2: Day 1, psoriatic plaque on left elbow of patient after 1 day oftreatment with ValDerm occlusion bandage after washing and drying.

FIG. 3: Day 5, psoriatic plaque on left elbow of patient after 4 daystreatment with ValDerm occlusion bandages renewed daily.

FIG. 4: Day 8, psoriatic plaque on left elbow of patient after 4 daystreatment with ValDerm occlusion bandages renewed daily.

DETAILED DESCRIPTION OF THE INVENTION

Anthracycline

Anthracyclines according to the present invention are a class ofantibiotics that are derived from an actinomycete of the genusStreptomyces as well as derivatives thereof. As anthracyclines arecapable of inhibiting DNA and/or RNA synthesis they are useful asantineoplastic agents and the group currently comprises more than 500species. Any anthracycline may be used with the present invention.

For example anthracyclines and/or derivatives thereof may be selectedfrom the group consisting of doxorubicin, valrubicin, epirubicin,daunorubicin, idarubicin, aclarubicin and5-iminodaunorubicin-dexrazoxane, pirarubicin, zorurubicin, amrubicinhydrochloride, N-acetyladriamycin and derivatives thereof.

In one embodiment of the present invention the anthracycline is selectedfrom the group of anthracyclines with the general formula

wherein R₁, and R₂ may individually be selected from the groupconsisting of —H, acyclic alkyls, cyclic alkyls, aryls, heteroaryls,alkenyls, alkynyls, alkoxyls, amines, hydroxyls, carboxyls,carboalkoxyls, esters, aryl esters, alkoxyl esters, amids, aryl amids,heterocycles and any of the aforementioned substituted with one or moreof hydroxyl, bromo, fluoro, chloro, iodo, mercapto, thio, cyano,alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carboalkoxyl, alkyl,alkenyl, nitro, amino, alkoxyl and/or amido.

For example R₁ and R₂ may individually be selected from the groupconsisting of —NH₂, C₁₋₁₀ alkoxyl, C₁₋₁₀ alkoxyl ester and C₁₋₁₀ alkoxylsubstituted with hydroxyl and/or amine and/or fluoro.

In one preferred embodiment, R₁ and R₂ are individually selected fromthe group consisting of:

-   -   —COCH₂OCO(CH₂)₃CH₃    -   —COCH₂OH    -   —COCH₃    -   —NH₂    -   —H    -   —OH    -   —NHCOCF₃

In one particularly preferred embodiment, R₁ is —COCH₂OCO(CH2)₃CH₃ andR₂ is —NHCOCF₃

Preferably, anthracyclines according to the present invention caninhibit and/or reduce proliferation of cells, such as for exampleproliferation of mammalian cells. This effect is preferably achieved dueto one or more of the following:

-   -   inhibition and/or reduction of DNA synthesis    -   inhibition and/or reduction of RNA synthesis    -   DNA Topoisomerase II inhibition    -   inhibition of nucleoside transport

Preferred anthracyclines according to the present invention arelipophilic anthracyclines. In particular, lipophilic anthracyclines arecapable of passing the cell membrane easily and may enter the cytoplasmand nucleus of cells in a fast manner.

One example of a lipophilic anthracycline is valrubicin, which is verylipophilic due to the less ionisation compared to other anthracyclines.Accordingly, valrubicin may pass the cell membrane easily and may enterthe cytoplasm of cells in a fast manner. Like other anthracyclines,valrubicin inhibits RNA and DNA synthesis.

Furthermore, preferred anthracyclines according to the present inventionare capable of penetrating into a multilayered epithelium, preferablymore than one cell layer, such as approximately 2 cell layers, forexample approximately 3 cell layers, such as approximately 4 celllayers, for example approximately 4 to 6 cell layers, such asapproximately 6 to 8 cell layers, for example approximately 8 to 10 celllayers, such as approximately 10 to 12 cell layers, for exampleapproximately 12 to 15 cell layers into a multilayered epithelium.Especially it is preferred that the anthracycline according to thepresent invention when applied to human skin surfaces can penetrate intoskin epithelium, more preferably, the anthracycline can penetrate 0.1 to0.2 mm, such as 0.2 to 0.3 mm, for example 0.3 to 0.5 mm, such as 0.5 to0.75 mm, for example 0.75 to 1.0 mm, such as 1.0 to 1.5 mm, for example1.5 to 2.0 mm, such as 2.0 to 2.5 mm, for example 2.5 to 3.0 mm such as3.0 to 3.5 mm, for example 3.5 to 4.0 mm, such as 4.0 to 4.5 mm, forexample 4.5 to 5.0 mm into the skin.

In addition, preferred anthracyclines according to the present inventionare systemically absorbed in a limited manner after topicallyadministration to a body surface.

Preferably, systemic absorption is less than 10%, such as less than 8%,for example less than 6%, such as less than 5% for example less than 4%,such as less than 3%, for example less than 2%, such as less than 1%.

Systemic absorption may be determined by any conventional method, forexample systemic absorption may be determined by measuring the amount ofanthracycline in a blood sample or in serum. Anthracycline in bloodand/or serum may for example be determined by HPLC.

Additionally, preferred anthracyclines according to the presentinvention are not locally toxic, when applied topically to a bodysurface of an individual, more preferably, the anthracyclines are not orare only mildly irritant when applied to a body surface of an individualin an effective dose (see herein below).

Histopathological animal experiments have shown that valrubicin does notaffect normal dermal epithelium (1-3) and that application of valrubicinto skin and eyes in a concentration similar to the concentration ofvalrubicin used in the treatment of bladder cancer only results in mildto no irritation (4). Furthermore, valrubicin is less cardiotoxic andhaematologically toxic than other anthracyclines (5; 6).

Accordingly, in one preferred embodiment of the present invention theanthracycline is valrubicin or a derivative thereof. Valrubicin, alsoknown as AD-32 or N-trifluoroacetyladriamycin-14-valerate, is asemisynthetic derivative of doxorubicin. In table 1 properties ofvalrubicin and doxorubicin are listed. TABLE 1 Pharmacodynamic and-kinetic properties of Valrubicin and Doxorubicin Valrubicin DoxorubicinMechanisms DNA binding − +++ DNA Topoisomerase II inhibition − (parent)++ ++ (metabolite) DNA Synthesis inhibition +++ (rapid) +++ (slow) RNASynthesis inhibition +++ (rapid) + (slow) Nucleoside TransportInhibition +++ + Pharmacology Cellular Uptake rate Rapid Slowlocalisation Cytoplasm Nucleus In vivo metabolism Extensive Minimal Invivo elimination rapid SlowBody Surface

A body surface according to the present invention is any surface of anindividual, which is easily accessible from the exterior of theindividual. The body surface preferably comprises an epithelium orconsists of an epithelium, which may comprise a monolayer of cells ormay be multilayered. However, the body surface preferably does notcomprise transitional epithelium.

For example the body surface may be selected from the group consistingof skin, mucosal membranes of the oral cavity, nose, vagina, eye,larynx, genital tract, lungs, bronchia, gastrointestinal tract andrectum. Preferably, the body surface is selected from the groupconsisting of skin, mucosal membranes of the oral cavity, nose, eye andvagina.

In one preferred embodiment the body surface is a mucosal membrane,preferably the mucosal membrane of the oral cavity.

In an especially preferred embodiment of the present invention, the bodysurface is the skin. Skin according to the present invention is composedof epidermis and dermis. The epidermis usually comprises 5 layers, whichfrom inside to outside is stratum basale, stratum spinosum, stratumgranulosum, stratum lucidum and strata corneum, wherein the stratumcorneum consists of keratinised cells. Each of these layers may compriseone or more cell layers. The dermis underlies the epidermis and is adense irregular connective tissue. The dermis may furthermore forexample comprise hair follicles, sweat glands and/or nerve endings. Theterm “skin” within the meaning of the present invention may comprise oneor more or all of the above mentioned layers and structures.

Conditions

The conditions to be treated according to the present invention are anycondition of a body surface associated with hyperproliferation and/orpre-neoplastic and/or neoplastic processes. Preferably, the condition isa condition, wherein hyperproliferation is a primary factor ofpathogenesis. More preferably, the clinical condition is associated withhyperproliferation of skin and/or mucosal membranes.

In one preferred embodiment of the present invention, the condition isassociated with dermal hyperproliferation and/or dermal pre-neoplasticand/or neoplastic processes. Dermal hyperproliferation may for examplebe hyperproliferation of epidermis or hyperproliferation of dermis.However, preferably dermal hyperproliferation is hyperproliferation ofthe epidermis. Hyperproliferation of epidermis may for example involvehyperproliferation of stratum basale.

However, the condition according to the present invention may also beassociated with hyperproliferation or pre-neoplastic or neoplasticprocesses of other body surfaces. Hence, a large number of differentconditions may be treated according to the present invention. Forexample the condition according to the present invention may be selectedfrom the group consisting of psoriasis, actinic keratosis, seborrheickeratosis, photo-induced keratosis, lichen planus, basocellularcarcinoma of the skin, planocellular carcinoma of the skin, leucoplakia,erythroplakia, carcinoma in situ in the mouth, verruca vulgaris,condyloma acuminata of skin or mucosal membranes, cutaneous T-celllymphomas, cutaneous metastasis and cicatricial hypertrophy.

In one embodiment the condition is cutaneous metastasis. The primarytumour from which the metastasis is derived may be any tumour; forexample the primary tumour may be breast cancer.

In one preferred embodiment the condition is psoriasis. The termpsoriasis according to the present invention includes all types ofpsoriasis known to the person skilled in the art. For example psoriasismay be selected from the group consisting of psoriasis vulgaris, guttatepsoriasis, flexural psoriasis, erythrodermic psoriasis, generalisedpustular psoriasis and localised pustular psoriasis. The psoriasis to betreated according to the present invention may be mild, moderate, moresevere or very severe psoriasis, such as psoriasis wherein less than 2percent, for example 2% to 5%, such as 5% to 10%, for example 10% to15%, such as more than 15% at the skin is affected.

Administration Forms

The individual to be treated according to the present invention ispreferably an individual suffering from a condition of a body surfaceassociated with hyperproliferation and/or pre-neoplastic and/orneoplastic processes, preferably one of the above mentioned conditions.The individual may be any animal, however, preferably the individual isa human being.

The treatment may be ameliorating treatment and/or the treatment may becurative treatment and/or the treatment may be prophylactic treatment.In some embodiments of the present invention, the treatment may abolishor relieve some or all of the symptoms of the condition during treatmentand/or for a specific period of time after cessation of treatment, butthen one or more symptoms may reappear. For example, the symptoms mayreappear about 1 day, such as about 2 days, for example about 3 days,such as about 3 to 5 days, for example about 5 to 7 days, such as about7 to 10 days, for example about 10 to 15 days, such as about 15 to 20days, for example about 20 to 30 days, such as about 30 to 60 days, forexample about 60 to 120 days, such as more than 120 days after cessationof treatment.

The pharmaceutical formulations according to the present invention arepreferably administered topically.

Topical administration according to the present invention should beunderstood as local administration directly to the site of disease.Preferably, topical administration results in that the majority of theactive compound i.e. anthracycline is not systemically absorbed andhence substantially only capable of exerting its effect locally at thesite of application. Preferably, systemic absorption is less than 10%,such as less than 8%, for example less than 6%, such as less than 5% forexample less than 4%, such as less than 3%, for example less than 2%,such as less than 1%.

The treatment may be administered once; however, the treatment isusually administered more than once, such as more than 2 times, forexample more than 5 times, such as mare than 10, for example more than15, such as more than 20, for example more than 30 times, such as morethan 50 times, for example more than 100 times, such as every timetreatment is required.

When the treatment is administered more than once, the individualadministrations may be distributed over a period of for example 1-2hours, such as 2-5 hours, for example 5-10 hours, such as 10-24 hours,for example 1-2 days, such as 2-5 days, for example 5-10 days, such as10-20 days, for example 20-30 days, for example 1-2 months, such as 2-5months; for example more than 5 months. In one preferred embodiment ofthe present invention, the individual administrations are distributedover a period of from 1 to 7 days, more preferably from 2 to 6 days,even more preferably from 3 to 5 days, most preferably around 4 days.

Furthermore, the time gap between two individual administrations may beless than 1 hour, or for example 1-2 hours, such as 2-5 hours, forexample 5-10 hours, such as 10-24 hours, for example 1-2 days, such as2-5 days, for example 5-10 days, such as 10-20 days, for example 20-30days, for example more than 1 month. The time gap between two individualadministrations may always be the same or it may different from time totime.

In one particular embodiment, treatment may be repeated at everyoccurrence and/or reoccurrence of the condition. At every occurrenceand/or reoccurrence of the condition, a treatment regimen may beadministered. Such a treatment regimen may comprise administration ofthe pharmaceutical composition once or more than once, such as more than2 times, for example 2 to 5 times, such as 5 to 10, for example 10 to15, such as 15 to 20, for example 20 to 30 times, such as more than 30times per treatment regimen.

Each treatment regimen may be administered over a period of for example1-2 hours, such as 2-5 hours, for example 5-10 hours, such as 10-24hours, for example 1-2 days, such as 2-5 days, for example 5-10 days,such as 10-20 days, for example 20-30 days, for example 1-2 months, suchas 2-5 months, for example more than 5 months.

The time gap between two individual administrations of a treatmentregimen may be less than 1 hour, or for example 1-2 hours, such as 2-5hours, for example 5-10 hours, such as 10-24 hours, for example 1-2days, such as 2-5 days, for example 5-10 days, such as 10-20 days, forexample 20-30 days, for example more than 1 month. The time gap betweentwo individual administrations of a treatment regimen may always be thesame or it may different from time to time.

The dose to be administered depends on the particular individual andcondition and severity of condition to be treated as well as the mode ofadministration. In general, however, between 1 μg and 5 mg ofanthracycline is administered.

In one embodiment, the anthracycline is administered in a dose ofpreferably 1 μg to 250 μg, more preferably 5 μg to 150 μg, even morepreferably 10 μg to 100 μg, yet more preferably 15 μg to 75 μg, evenmore preferably 20 μg to 50 μg, yet more preferably 25 μg to 40 μg, evenmore preferably 25 μg to 35 μg, most preferably around 30 μg ofanthracycline per dose. Such administration doses are for examplesuitable for administration in an occlusion bandage or for otheradministration forms.

In another embodiment, the anthracycline is administered in apharmaceutical formulation that comprises from 0.01% to 10%, such asfrom 0.05% to 8%, for example from 0.1% to 7%, such as from 0.25% to 6%,for example from 0.5% to 5%, such as from 0.6% to 4%, for example from0.7% to 2%, such as from 0.75% to 1.5%, for example from 0.8% to 1.2%W/W anthracycline. Furthermore, the anthracycline may be administered ina pharmaceutical formulation that comprises from 0.01% to 0.05%, such asfrom 0.05% to 0.1%, for example from 0.1% to 0.25%, such as from 0.25%to 0.5%, for example from 0.5% to 0.75%, such as from 0.75% to 1.0%, forexample from 1.0% to 1.25%, such as from 1.25% to 1.5%, for example from1.5% to 2.0% w/w anthracycline. Such administration doses are forexample suitable when the anthracycline is administered formulated as asolution, gel, ointment, creme, lotion or in any other form suitable fortopical administration.

In one embodiment the anthracycline is administered in an ointment thatcomprises around 1% or such as around 0.7% or for example around 0.5%w/w anthracycline.

Preferably, administration of the pharmaceutical compositions accordingto the present invention does not result in any severe malaise or anysevere irritation, more preferably administration does not result in anysignificant nuisance to the individual to be treated, most preferably,administration does result in only mild and/or no malaise, irritationand/or nuisance.

Pharmaceutical Compositions

The pharmaceutical compositions according to the present inventionpreferably comprise at least one anthracycline together with one or moresuitable pharmaceutically acceptable carriers. The pharmaceuticalcompositions according to the present invention are preferablyformulated in a manner suitable for topical administration to a bodysurface.

The pharmaceutical composition according to the present invention maycomprise more than one different anthracycline, such as 2, for example3, such as 4, for example 5, such as more than 5 differentanthracyclines.

The pharmaceutical composition may be formulated in a number ofdifferent ways dependent on the condition to be treated, the individualto be treated and the site of disease. Accordingly, the pharmaceuticalcomposition is preferably formulated according to the need of thespecific embodiment of the present invention.

For example the pharmaceutical composition may be selected from thegroup consisting of a suspension, solution, ointment, lotion, sexuallubricant, cream, foam, aerosol, spray, suppository, implant, inhalant,dry powder, syrup, balm and lozenge. Preferably however, thepharmaceutical composition may be selected from the group consisting ofa lotion, an ointment, a gel, a cream, a transdermal patch, an occlusionbandage comprising a solution and/or suspension comprising theanthracycline and a spray.

In one preferred embodiment the pharmaceutical composition is formulatedas a solution, ointment, lotion, cream or a gel. In particular, when thecondition is psoriasis or another condition of the skin, it is preferredthat the pharmaceutical composition is formulated as an ointment,lotion, cream or gel.

Pharmaceutical compositions containing an anthracycline according to thepresent invention may be prepared by conventional techniques, e.g. asdescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19^(th) edition,Easton, Pa.

Pharmaceutically acceptable salts of the compounds according to thepresent invention should also be considered to fail within the scope ofthe present invention. Pharmaceutically acceptable salts are prepared ina standard manner, If the parent compound is a base, it is treated withan excess of an organic or inorganic acid in a suitable solvent. If theparent compound is an acid, it is treated with an inorganic or organicbase in a suitable solvent.

The compounds of the invention may be administered in the form of analkali metal or earth alkali metal salt thereof, concurrently,simultaneously, or together with a pharmaceutically acceptable carrieror diluent.

Solutions, creams, ointments or gels according to the present inventionare semisolid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient in finelydivided or powdered form, alone or in solution or suspension in anaqueous or non-aqueous fluid, with the aid of suitable machinery, with agreasy or non-greasy base, such as known to the person skilled in theart.

Examples of bases are bases that may comprise one or more hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, paraffin oil, beeswax,a metallic soap; a mucilage; an oil of natural origin such as almond,corn, arachis, castor or olive oil or derivatives thereof such as castoroil polyoxyl; wool fat or its derivatives or a fatty acid and/or estersuch as steric or oleic acid, or isopropyl myristate.

The base may furthermore comprise an alcohol such as propylene glycol,polyethylene glycol (PEG) of different molecular weights, cetyl alcohol,ethanol or a macrogel. The formulation may incorporate any suitablesurface active agent or emulsifier such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester, polysorbate, CremophorEL, Tween 20, or a polyoxyethylene derivative thereof. Suspending agentssuch as natural gums, cellulose derivatives or inorganic materials suchas silicaceous silicas, and other ingredients such as lanolin, may alsobe included.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby standard methods. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturiser such as glycerol or an oilsuch as castor oil or arachis oil.

In one preferred embodiment, the pharmaceutical formulations accordingto the pre-sent invention comprise one or more compounds selected fromthe group consisting of emulsifiers, hydroxy compounds and lipids. Forexample 2 compounds, such as 3 compounds, for example more than 3compounds.

The emulsifier may be any emulsifier known to the person skilled in theart that is suitable for pharmaceutical formulations for topicaladministration. Preferably, the emulsifier is selected from the groupconsisting of Cremophor EL, Tween 20, polysorbate 80 and mixturesthereof, more preferably, the emulsifier is polysorbate 80. However, itis also contained within the present invention that the pharmaceuticalcomposition comprises more than one emulsifier.

The hydroxy compound may be any hydroxy compound known to the personskilled in the art that is suitable for pharmaceutical formulations fortopical administration. The pharmaceutical formulation may comprise morethan one different hydroxy compound, such as 2, for example 3, such as4, for example 5, such as 6, for example more than 6. Preferably, thehydroxy compound is selected from the group consisting of ethanol,glycerol, propylene glycol, polyethylene glycol (PEG), cetyl alcohol andmixtures thereof. PEG may be any molecular weight PEG, preferablyhowever PEG 6000. More preferably, the hydroxy compound is selected fromthe group consisting of ethanol, glycerol, propylene glycol, PEG 6000and cetyl alcohol.

The lipid may be any lipid known to the person skilled in the art thatis suitable for pharmaceutical formulations for topical administration.The term lipid as used herein comprises fatty acids and esters thereof.Preferably, the lipid is selected from the group consisting of fattyalcohols, fatty acid esters, mineral oil, oil of natural origin andderivatives thereof and mixtures thereof. More preferably the lipid isselected from the group consisting of Castor oil polyoxyl, paraffin oiland isopropyl myristate. The pharmaceutical composition according to thepresent invention may comprise only one kind of lipid or it may comprisemore than one kind, such as 2, for example 3, such as more than 3different lipids.

Examples of specific formulations according to the present invention aregiven in the examples herein below.

Combination Therapy

The pharmaceutical compositions according to the present invention maycomprise one or more different active components in addition to theanthracycline, such as one, for example 2, such as 3, for example 4,such as 5, for example more than 5 different active components.

In one preferred embodiment the pharmaceutical composition furthermorecomprises a second active component. The second active component may beany active component known to the person skilled in the art. In aparticularly preferred embodiment, the second active component isselected from the group of active components, which are known to beactive against the condition to be treated.

Accordingly, when the condition is psoriasis, the second activecomponent may be a component which is known in the art to be effectiveagainst psoriasis. For example the second active component may beselected from the group consisting of steroids, coal tar, calcipotriene,vitamin A, antralin and salicylic acid.

The methods of treatment disclosed by the present invention may also becombined with one or more second treatments. In one embodiment of thepresent invention, the second treatment may be treatment with adifferent anthracycline, so that the method comprises treatment with 2,for example 3, such as 4, for example 5, such as more than 5 differentanthracyclines.

However, the second treatment according to the present invention mayalso be treatment which is not administration of an anthracycline.Preferably, the second treatment(s) may be selected from the group oftreatments, which are known to be active against the condition to betreated.

Accordingly, when the condition is psoriasis the second treatment may bea treatment, which is known in the art to be effective againstpsoriasis. For example the second treatment may be selected from thegroup consisting of treatment with sunlight, ultraviolet light B (UVB)or PUVA. In particular, the anthracycline according to the presentinvention may sensitise the individual towards treatment with sunlight,ultraviolet light B (UVB) or PUVA, in a manner such as lower amount oflight and/or irradiation is required to obtain the desired effect.Furthermore, the second treatment may be administration of at least onecompound selected from the group consisting of steroids, coal tar,calcipotriene, vitamin A, anthralin, salicylic acid, methotrexate,retinoids and cyclosporin.

The anthracycline and the second treatment may be administeredsimultaneously or sequentially in any order. In one embodiment, thetreatments are administered in a rotational manner, such as onetreatment is administered for a specific predetermined amount of time,after which the second treatment is administered for a specificpredetermined amount of time, after which the first treatment isadministered again and so forth. Rotational treatment may also comprisemore than 2, such as 3, for example 4, such as 5, for example more than5 different treatments.

Each of the different treatments may be given once or more than once asdescribed for the anthracyclines herein above.

When the condition is a neoplastic and/or preneoplastic condition, suchas for example a cutaneous metastasis the second treatment may be anytreatment known in the art to be effective against neoplastic and/orpreneoplastic conditions.

For example the second treatment may be chemotherapy, including systemicor topical administration of any suitable cytostatica known to theskilled person. Furthermore the second treatment may be selected fromthe group consisting of surgical treatment, radiation therapy, therapywith cytokines, hormone therapy, gene therapy, dendritic cell therapyand treatments using laser light.

In one embodiment, the second therapy is preferably radiation therapy,more preferably radiation therapy comprising electron and/or photonirradiation. In particular, topical administration of anthracycline maysensitise locally against irradiation, so that radiation therapy maybecome more efficient.

EXAMPLES

The examples given herein are illustrative examples of embodiments ofthe present invention and should not be regarded as limiting for theinvention.

Example 1 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

ValDerm Solution

A composition of the following ingredients; % Valrubicin 1 Castor oilpolyoxyl Ph.Eur. 10 Ethanol anhyd. 39 Glycerol anhyd. 50 Total 100was prepared by dissolving Valrubicin in the mixture of Castor oilpolyoxyl Ph. Eur. and Ethanol anhyd. Thereafter Glycerol anhyd. isadded.

The following solution was prepared as described above. ValDerm (0.267mg/g) Valrubicin 40 mg/ml 0.5 ml Cremophor El 8.6 ml Ethanol 11.4 ml Glycerol anhyd.  55 ml Placebo Cremophor El 8.6 ml Ethanol 11.4 ml Glycerol anhyd.  55 ml

Example 2 Treatment of Psoriasis Vulgaris

Either 5 drops of placebo (see example 1) or 5 drops of ValDerm (seeexample 1) were placed on waterproof occlusion bandages (OpSite,Post-Op, Smith+Nephew, 6.5 cm×5 cm). Subsequently, the occlusionbandages were placed on the left elbow (ValDerm) and the right elbow(placebo) on a patient suffering from psoriasis vulgaris, said patienthaving large, visible psoriatic plaques at both elbows at the time whentreatment was initiated.

The occlusion bandages were renewed daily. When bandages were renewed,remains of old administered substance was removed and toxicology wasestimated, before placing a fresh occlusion bandage with fresh ValDermor Placebo. The condition of the elbows and knee was documented bydigital photography (Kodak DC 265, 1.2 megapixel) with automatic timestamp on all pictures. Pictures were reduced to 12×8 cm and printed on aHP deskjet 970Cxi printer on premium glossy photo paper.

The treatment was administered for 4 days.

There was a clear effect of Valderm after 4 days treatment as shown inFIG. 1 to 4 including smoothening of the treated psoriatic plaques aswell as healing with normal looking skin. On day 0 before treatment wasinitiated, there were clear psoriatic plaques on left elbow (FIG. 1), onday 1 after 1 day of treatment the psoriatic plaques had already becomeless pronounced (FIG. 2), on day 5 after 4 days of treatment thepsoriatic plaques had largely disappeared (FIG. 3) and on day 8 after 4days of treatment, a further improvement compared to day 5 was observedwith increased healing of the psoriatic plaque (FIG. 4).

Around 21 days after cessation of treatment, the psoriatic plaques hadreappeared at a size similar to prior to treatment. No rebound phenomenawere observed.

The patient was questioned daily about irritation and other side effectsof the treatment. The patient did not feel any malaise or irritation atthe site of treatment and the patient did not feel any difference innuisance after treatment with placebo versus ValDerm.

Example 3 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 1 Castor oil polyoxyl Ph.Eur. 10 Ethanol 39 Glycerolanhyd. 50 Total 100

Example 4 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 1 Polysorbate 20 10 Ethanol 39 Glycerol anhyd. 50Total 100

Example 5 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 2 Castor oil polyoxyl Ph.Eur. 5 Polysorbate 20 5Ethanol 38 Glycerol anhyd. 50 Total 100

Example 6 Pharmaceutical Gel for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 1 Polysorbate 20 10 Ethanol 40 Polyethylene glycol6000 49 Total 100

Example 7 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 1 Castor oil polyoxyl Ph.Eur. 15 Ethanol 54 Propyleneglycol 30 Total 100

Example 8 Pharmaceutical Solution for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 0.5 Castor oil polyoxyl Ph.Eur. 5 Ethanol 30 Glycerolanhyd. 39.5 Propylene glycol 20 Isopropyl myristate 5 Total 100

Example 9 Pharmaceutical Composition for Topical AdministrationComprising Valrubicin

% (w/w) Valrubicin 1 Castor oil polyoxyl Ph.Eur. 5 Polysorbate 20 5Ethanol 35 Glycerol anhyd. 49 Paraffin oil 5 Total 100

Example 10 Pharmaceutical Gel for Topical Administration ComprisingValrubicin

% (w/w) Valrubicin 0.7 Castor oil polyoxyl Ph. Eur. 7 Ethanol 35Glycerol anhydrate 32.3 Polyethylene glycol 6000 20 Cetyl alcohol 5Total 100

Example 11 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as asolution (ref ex, 5) at a concentration of 2% (weight/weight) and wasapplied to the affected skin once daily. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

Example 12 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as asolution (ref ex. 8) at a concentration of 0.5% (weight/weight) and wasapplied to the affected skin once daily. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

Example 13 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as agel (ref ex. 6) at a concentration of 1% (weight/weight) and was appliedto the affected skin once daily. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

Example 14 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as asolution (ref. ex 5) at a concentration of 2.0% (weight/weight) and wasapplied to the affected skin twice daily. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

Example 15 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as asolution (ref. ex 5) at a concentration of 2.0 (weight/weight) and wasapplied to the affected skin twice a week. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

Example 16 A Clinical Trial, Topical Therapy of Psoriasis Vulgaris

A patient having dermal manifestations of psoriasis vulgaris wasselected for therapy using the invention. Valrubicin was prepared as asolution (ref. ex 5) at a concentration of 2.0% (weight/weight) and wasapplied to the affected skin once a week. The patient was monitored forimprovement in his manifestations of psoriasis. After the skin lesionshad subsided, therapy was discontinued.

REFERENCES

-   (1) Dantchev D, Slioussartchouk V, Paintrand M, Hayat M, Bourut C,    Mathe G. Electron microscopic studies of the heart and light    microscopic studies of the skin after treatment of golden hamsters    with adriamycin, detorubicin, AD-32, and aclacinomycin. Cancer Treat    Rep 1979; 63(5):875-888.-   (2) Dantchev D, Slioussartchouk V, Paintrand M, Bourut C, Hayat M,    Mathe G. Ultrastructural study of the cardiotoxicity and    light-microscopic findings of the skin after treatment of golden    hamsters with seven different anthracyclines. Recent Results Cancer    Res 1980; 74:223-249.-   (3) Dantchev D, Balercia G, Bourut C, Anjo A, Maral R, Mathe G.    Comparative microscopic study of cardiotoxicity and skin toxicity of    anthracycline analogs. Biomed Pharmacother 1984; 38(7):322-328.-   (4) Expert report. 21. Ref Type: Generic-   (5) Onrust S V, Lamb H M. Valrubicin. Drugs Aging 1999; 15(1):69-75.-   (6) Sweatman T W, Parker R F, Israel M. Pharmacologic rationale for    intravesical N-trifluoroacetyladriamycin-14-valerate (AD 32): a    preclinical study. Cancer Chemother Pharmacol 1991; 28(1):1-6.-   (7) FDA. Valstar (Valrubicin) Sterile Solution. 2001.

1. A pharmaceutical composition comprising an lipophilic anthracyclinetogether with one or more pharmaceutically acceptable carriers, whereinsaid pharmaceutical composition is formulated for topical administrationto a body surface and wherein said lipophilic anthracycline has a higherlipophilicity than doxorubicin when their lipophilicities are comparedunder the same conditions.
 2. The pharmaceutical composition accordingto claim 1, wherein the lipophilic anthracycline is valrubicin.
 3. Thepharmaceutical composition according to claim 1, wherein the bodysurface is the skin.
 4. The pharmaceutical composition according toclaim 1, wherein the body surface is the oral cavity.
 5. Thepharmaceutical composition according to claim 1, wherein thepharmaceutical composition is selected from the group consisting of alotion, an ointment, a gel, a cream, a transdermal patch, an occlusionbandage comprising a solution and/or suspension comprising thelipophilic anthracycline and a spray.
 6. The pharmaceutical compositionaccording to claim 1, wherein the pharmaceutical composition furthermorecomprises a second active component.
 7. The pharmaceutical compositionaccording to claim 6, wherein the second active component is selectedfrom the group consisting of steroids, coal tar, calcipotriene, vitaminA, anthralin and salicylic acid.
 8. The pharmaceutical compositionaccording to claim 1, wherein at least one pharmaceutically acceptablecarrier is selected from the group consisting of emulsifiers, hydroxycompounds and lipids.
 9. The composition of claim 1 wherein saidlipophilic anthracycline has a lipophilicity higher than that ofdoxorubicin, daunorubicin, epirubicin and idarubicin.
 10. Apharmaceutical composition comprising an lipophilic anthracyclinetogether with one or more pharmaceutically acceptable carriers, whereinsaid pharmaceutical composition is formulated for topical administrationto a body surface and wherein said lipophilic anthracycline is notdoxorubicin, daunorubicin, epirubicin or idarubicin.